The Kerala-Einstein Study (KES) proposes to build on the successful activities in our previous funding period to conduct high quality and impact research into Alzheimer?s disease and related dementias in the southern Indian state of Kerala. The KES team successfully established clinical research center in Kerala, trained junior investigators, instituted uniform study procedures, developed culture-fair cognitive tests, built databases, created research neuroimaging protocols, established a biorepository, and had multiple publications. In this renewal, our focus is on risk factors and brain substrates of pre-dementia syndromes, especially Motoric Cognitive Risk syndrome (MCR). MCR is a recent and innovative concept proposed by Dr. Verghese and colleagues, and validated in multiple countries including low and middle-income countries (LMIC). MCR is a pre-dementia syndrome characterized by presence of cognitive complaints and slow gait. MCR predicts risk of both Alzheimer?s disease and vascular dementia even after accounting for overlap with Mild Cognitive Impairment syndrome (MCI). Unlike MCI, complex cognitive tests or assays are not needed to diagnose MCR, increasing its clinical utility in resource poor LMIC settings. Aim 1. Examine clinical risk factors for pre-dementia syndromes (MCR and MCI) in 1000 Kerala seniors. We identified potentially modifiable risk factors (depression, sedentariness and obesity) for MCR in developed countries, but their association with MCR in LMIC is unknown. In addition, we will study novel risk factors for pre- dementia syndromes in India; apathy and mild traumatic brain injury, and cognitive reserve. Aim 2. Explore risk factors for pre-dementia syndromes in 400 rural and 600 urban Kerala seniors. There is a paucity of cognitive studies in rural seniors globally; our urban and rural sites in Kerala will provide a valuable opportunity to compare and contrast risk factors for MCR and MCI. In this renewal, we propose to establish a new research center in a rural site. Aim 3. Establish brain pathologies and substrates of MCR in Kerala seniors. Frontal lacunes and frontal gray matter thinning were associated with MCR in KES, implicating both vascular and neurodegenerative pathologies. Small vessel disease is associated with gray matter atrophy. We propose to test mechanistic hypotheses linking these two pathologies to MCR syndrome in 400 indivdiuals with neuroimaging. We will continue to examine the neurobiological basis of pre-dementia syndromes in the KES biorepository that contains genetic samples of over 500 clinically phenotyped patients (normal, MCI and dementia). Our studies have the potential to continue to have a major impact in continuing to build sustainable research capacity in India, foster research training in India and USA and elucidate the pathogenesis of dementia.